Drug delivery endovascular stent and method of use

ABSTRACT

An improvement in drug-eluting stents, and method of their making, are disclosed. The surface of a metal stent is roughened to have a surface roughness of at least about 20 μin (0.5 μm) and a surface roughness range of between about 300-700 μin (7.5-17.5 μm). The roughened stent surface is covered with a polymer-free coating of a limus drug, to a coating thickness greater than the range of surface roughness of the roughened stent surface.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 60/853,077, filed Oct. 20, 2006, and U.S. patentapplication Ser. No. 11/751,268, filed May 21, 2007, both of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present application relates to an endovascular stent at least partlyincluding a textured or abraded surface, and a method of making andusing the stent.

BACKGROUND

Complications such as restenosis are a recurring problem in patients whohave received artherosclerosis therapy in the form of medical proceduressuch as percutaneous translumenal coronary angioplasty (PTCA).Restenosis is commonly treated by a procedure known as stenting, where amedical device is surgically implanted in the affected artery to preventit from occluding post procedure.

A stent is typically cylindrical in shape and is usually made from abiocompatible metal, such as cobalt chromium or surgical steel. Moststents are collapsible and are delivered to the occluded artery via atranslumenal catheter. The stent is affixed to the catheter and can beeither self expanding or expanded by inflation of a balloon inside thestent that is then removed with the catheter once the stent is in place.

Complications that can arise from stent therapy include restenosis andthrombosis. In an effort to overcome these complications, stents maycontain a layer or coating of an anti-restenosis drug that is releasedin a controlled fashion at the stent-implantation site. Typically, thedrug is contained in a permanent or bioerodable polymer carrier, asdisclosed, for example, in U.S. Pat. No. 5,716,981 issued to Hunterentitled “Anti-angiogenic Compositions and Methods of Use.” Examples oftypical therapies that are proposed to be delivered in this manner areantiproliferatives, anticoagulants, anti-inflammatory agents andimmunosuppressive agents, although there are many other chemical andbiological agents also mentioned in the patent literature. It has beensuggested that the polymer carrier with drug may be covered by a porousbiodegradable layer that serves to regulate controlled release of thedrug into the body, as disclosed for example, in U.S. Pat. Nos.6,774,278 and 6,730,064.

More recently, stents in which an anti-restenosis drug is carried inchannels, grooves or pores for release in “polymer-free” i.e. pure-drugform have been proposed. Alternatively, stents having roughened surfaceintended to anchor a drug layer on the surface of the stent, for releasein pure-drug form have been proposed, for example, in U.S. Pat. Nos.6,805,898 and 6,918,927. None of these patents show or suggest that withparticular classes of anti-restenosis compounds, it is possible toenhance the anti-restenosis activity of the compounds by selection ofsurface roughness features within certain ranges on the stent surface.

In light of the complications associated with stent therapy, it would bedesirable to develop a stent having at least one roughened or texturedsurface for increased surface area, which can be manufactured in such away as to maximize structural integrity, drug loading capacity, andability to deliver drug to the vessel wall in a therapeutically enhancedway, as evidenced by a reduced risk of rate of occurrence or extent ofrestenosis following stent placement at the site of vascular injury.

SUMMARY

The invention includes, in one embodiment, an improvement in a methodfor reducing the rate of occurrence and/or extent of restenosis orthrombosis resulting from vascular injury in a subject, relative to thatobserved by placing at the site of injury, a smooth-surfaced expandablestent formed of interconnected metal filaments, by coating the outersurface of the stent filaments with a polymer carrier containing a limusdrug. The improvement, which is intended to maintain or further reducethe rate of occurrence and/or extent of restenosis or thrombosis,relative to that achieved with a polymer-coated, limus-eluting stent,but without the presence of a polymer carrier, includes the steps of:

(a) roughening outer surface regions of the stent filaments to a surfaceroughness of at least about 20 μin (0.5 μm), and a surface roughnessrange (maximum peak-to-valley) of between about 300-700 μin (7.5-17.5μm), and

(b) coating the roughened regions of the stent filaments with apolymer-free coating of the limus drug, to a coating thickness greaterthan the surface roughness range of the roughened stent surface, thatis, to a thickness that covers the roughened surface.

The stent filaments may be roughened to have a surface roughness ofbetween about 20-40 μin (0.5 to 1 μm), and/or a surface roughness rangeof between about 300-500 μin (7.5-12.5 μm).

The surface roughening may be carried out by abrading the outer surfaceregions of the stent filaments with a pressurized stream of abrasiveparticles, by forming a hydrocarbon-film mask over outer surface regionsof the stent filaments, selectively removing stent material exposed bythe mask, and removing the mask, by laser etching the outer surfaceregions of the stent filaments, or by peening the outer surface regionsof the filaments to imprint a pattern thereon.

The drug coating may be applied as a viscous solution of the drug ontothe outer surfaces of the stent filament, with drying to form a soliddrug coating on the stent filaments. The coating may be applied to afinal amount of limus drug on the stent between 25 to 240 ug/cm stentlength, and to a final coating thickness between 5 and 15 μm. Onepreferred class of limus drugs are the 42-0-alkoxyalkyl limus compounds,as exemplified by the 42-O-ethoxyethyl compound referred to herein asBiolimus A9™.

In another aspect, the invention includes an improvement in a method foradministering an anti-restenosis drug from an expandable stent formed ofinterconnected metal filaments, by coating the outer surface of thestent with a polymer-free limus drug coating. The improvement, which isintended to reduce the rate of occurrence and/or extent of restenosis orthrombosis achieved with the polymer-free limus drug coating, comprisesroughening the outer surface regions of the stent filaments which arecoated by the limus drug, to a surface roughness of at least about 20μin (0.5 μm), and a surface roughness range of between about 300-700 μin(7.5-17.5 μm).

Also disclosed is an expandable stent for use in reducing the rate ofoccurrence and/or extent of restenosis or thrombosis resulting when thestent is placed at a site of vascular injury. The stent includes anexpandable stent body formed of interconnected metal filaments, andformed on outer surface regions of the stent filaments, a roughenedsurface characterized by a surface roughness of at least about 20 μin(0.5 μm), and a surface roughness range of between about 300-700 μin(7.5-17.5 μm), and carried on the roughened regions of the stentfilaments, a polymer-free coating of the limus drug having a coatingthickness greater than the range of surface roughness of the roughenedstent surface.

These and other aspects and embodiments of the present invention willbecome better apparent in view of the detailed description inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scanned image of an endovascular stent having a metalfilament body;

FIG. 2A is a scanning electron micrograph of an abraded stent surface;

FIG. 2B is a scanning electron micrograph of the surface of FIG. 2Ashowing quantification of peaks generated on the stent surface afterabrasion;

FIG. 2C is a scanning electron micrograph of the surface of FIG. 2Ashowing quantification of valleys generated on the stent surface afterabrasion;

FIG. 3A is an illustration of a pneumatic press treating a stentsurface;

FIG. 3B is a close up frontal view of the fixed-head punch assembly ofFIG. 3A showing the pneumatic press with multiple peeners;

FIG. 3C is close up side view of the fixed head punch assembly of FIG.3B;

FIG. 3D is a close up frontal of the fixed-head attachment for the punchassembly of the pneumatic press of FIG. 3A showing an exemplary pattern;

FIG. 4 is a scanning electron micrograph of a drug-coated, treatedstent;

FIG. 5 is an elution profile of the drug Biolimus A9™ from the presentstent and the Biomatrix® II stent as measured by the percentage of thetotal amount of drug released over cumulative time in hours;

FIG. 6 is a graph showing the percentage of the drug Biolimus A9™released from the present stent and a Biomatrix® II in a porcine implantmodel at three and two months, respectively;

FIG. 7 is a graph showing the peak concentration in ng/mL of the drugBiolimus A9™ in peripheral blood over time in hours as released from thepresent stent and a Biomatrix® II stent in a porcine implant model asmeasured by mass spectroscopy;

FIG. 8 is a graph showing the percentage of area occlusion for a stenthaving no drug and a stent having the Biolimus A9™ drug;

FIGS. 9A-9F are scanned images of histological sections of a vessel 28days after implantation of a bare-metal stent (FIGS. 9A-9B), ametal-filament stent with a polymer coating containing Biolimus A9™(FIGS. 9C-9D), and metal-filament microstructure stent with a coating ofBiolimus A9™ (FIGS. 9E-9F); and

FIGS. 10A-10K are graphs of the histomorphometry of an explanted vesselcontaining the microstructure stent.

DETAILED DESCRIPTION I. Definitions

Unless indicated otherwise, the terms below have the following meaningsherein.

“Surface roughness” or “roughness average” or “Ra” is the arithmeticaverage of absolute values of the measured profile height deviationstaken within the sampling length or area measured from the graphicalcenterline or centerplane (the mean line or plane). It is measuredtypically by a non-contact surface optical profilometer, as discussedbelow, but may also be measured by a contact profilometer or byestimating peak and valley heights from a surface micrograph.

“Surface roughness range” or “Rt” is the maximum peak-to-valleydistance, calculated as the sum of the maximum peak and maximum valleymeasurements of roughness with respect to a centerline or centerplane.It is typically measured by non-contact surface optical profilometer,but can also be measured by the other methods noted above.

“Limus drug” refers to a macrocyclic triene immunosuppressive compoundhaving the general structure shown, for example, in U.S. Pat. Nos.4,650,803, 5,288,711, 5,516,781, 5,665,772 and 6,153,252, in PCTPublication No. WO 97/35575, in U.S. Pat. No. 6,273,913B1, and in U.S.Patent Application/Publication Nos. 60/176,086, 2000/021217A1, and2001/002935A1.

“42-O-alkoxyalkyl limus drug” refers to the 42-O alkoxyalkyl derivativeof rapamycin described in U.S. patent application publication no.20050101624, published May 12, 2005, which is incorporated herein in itsentirety. For example, “42-O-alkoxyalkyl limus drug” is“42-O-ethoxyethyl rapamycin,” also referred to herein as “Biolimus A9.”

“Polymer-free coating” means a coating whose structure and cohesivenessare provided by the drug itself, with or without the presence of one ormore binding agents, rather than by a polymer matrix in which the drugis embedded, i.e., a polymer carrier.

II. Endovascular Stent

FIG. 1 shows a stent constructed in accordance with the invention, inthe stent's contracted state. The stent includes a structural member orbody with at least one surface being at least partly roughened orabraded at least for holding and releasing an anti-restenosis compound,as will be described further below.

In the embodiment shown, the stent body is formed of a series of tubularmembers called struts 3 connected to each other by filaments calledlinkers 4. Each strut 3 has an expandable zig-zag, sawtooth, helicalribbon coil or sinusoidal wave structure, and the connections to eachlinker 4 serve to increase overall stent flexibility. Thecontracted-state diameter of the stent is between approximately 0.5mm-2.0 mm, preferably 0.71 to 1.65 mm, and a length of between 5-100 mm.The expanded stent diameter is at least twice and up to 8-9 times thatof the stent in its contracted state, for example, a stent with acontracted diameter of between 0.7 to 1.5 mm may expand radially to aselected expanded state of between 2.0-8.0 mm or more. Stents havingthis general stent-body architecture of linked, expandable tubularmembers are known, for example, as described in PCT Publication No. WO99/07308, which is commonly owned with the present application andexpressly incorporated by reference herein.

Preferably, the stent structure is made of a biocompatible material,such as stainless steel. Further examples of biocompatible materialsthat are typically used for the stent structure are, cobalt chromium,nickel, magnesium, tantalum, titanium, nitinol, gold, platinum, inconel,iridium, silver, tungsten, or another biocompatible metal, or alloys ofany of these; carbon or carbon fiber; cellulose acetate, cellulosenitrate, silicone, polyethylene teraphthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; poly-L-lactic acid, poly-DL-lacticacid, polyglycolic acid or copolymers thereof, a polyanhydride,polycaprolactone, polyhydroxybutyrate valerate or another biodegradablepolymer, or mixtures or copolymers of these; a protein, an extracellularmatrix component, collagen, fibrin or another biologic agent; or asuitable mixture of any of these. An example of a typical stent isdescribed in U.S. Pat. No. 6,730,064. The dimensions of each stent willvary depending on the body lumen in which they are to be delivered. Forexample, a stent may have a diameter ranging from approximately 0.5 mmto approximately 25.0 mm and a length that ranges from approximately 4mm to approximately 100 mm or longer. An example of stent measurementsis described in co-owned U.S. Pat. No. 6,939,376, which is commonlyowned and expressly incorporated by reference herein.

As seen in FIG. 2A, at least a portion of at least one of the surfacesof the stent has a roughened or abraded microstructure or texturedsurface 12. This microstructure can include at least one therapeuticagent that elutes from the microstructure. As seen in FIGS. 2B-2C, theroughened or textured surface 12 provides interstices or verticallyprojecting surface features and/or regions of undercuts or recesses 16.It will be appreciated that a solution containing a therapeutic agentcan be drawn, e.g., by capillary forces into such recesses 16 and coatthe projecting surfaces. In this manner, the surface area for coatingthe stent may be increased. The thickness of such layer refers to theaverage thickness of the layer, e.g., average depth of the infusibleportion of the layer. Preferably, and as seen in FIG. 2A, at least aportion of the ablumenal surface of the stent, i.e., the surface incontact with the treated vessel after stent placement, includes themicrostructure surfacing.

III. Methods of Preparing Textured Surface

In one embodiment, not shown, the method includes use of a mask toprevent at least a portion of the stent from being abraded. Preferably,the mask is a hydrocarbon film, such as PARAFILM®, however, it will beappreciated that any suitable barrier to abrasion is suitable for use inthese methods. Accordingly, in a preferred embodiment, at least thelumenal surface of the stent is not abraded. In one embodiment, a sheetof the mask approximately 5 mm by 60 mm is rolled around the diameter ofa mandrel such as a 1.4 mm glass capillary tube. The stent is positionedonto the mandrel and hand-crimped into the hydrocarbon mask. A stereomicroscope set between 10× and 40× may be used to ensure that theportion of the stent that is not to be abraded is covered by the mask.In a preferred embodiment, at least 80% of the stent wall thickness onall surfaces is masked by the hydrocarbon film layer.

In one embodiment, the stent surface 5 is then treated by utilizingmicroblasting systems, not shown, such as the MICRO BLASTER® andPROCENTER® by Comco, Inc. or an equivalent. In one embodiment, 25 μm ofan abrasive, such as aluminum oxide, is used to roughen the stentsurface 5. The pressure is adjusted to 40 psi±5 psi, and a spray nozzleis positioned approximately 2.5 cm to 5.0 cm from the stent surface 5,making multiple passes over the stent.

In another embodiment, the mask is removed by any appropriate means suchas via ultrasonic cleaning, not shown. Typically the ultrasonic cleaneris filled with deionized water which is heated to 45° C. A sample vialof HPLC grade chloroform is heated to between 50-60° C. on a hotplate. Aglass capillary tube mandrel with a treated stent is incubated in a vialof 40° C. and 50° C. HPLC grade chloroform for 5-10 minutes. The vialcontaining the chloroform and mandrel is then sonicated in 45° C.deionized water for two minutes.

Due to the roughening of the stent surface 5, different elements areexpressed on the metal surface, which can increase the susceptibility tocorrosion. As a result, the treated stent is generally passivatedaccording to ASTM standards and cleaned in a series of solvents such asChloroform, Acetone and/or Isopropyl Alcohol. In one embodiment, afterthe mask is removed and the treated stent is sonicated, it is removedfrom the vial of chloroform. A sample vial is rinsed with Acetone andthen refilled with Acetone. The treated stent is placed in the vial andsonicated in the ultrasonic cleaner for two minutes. The vial is rinsedwith isopropyl alcohol and then refilled with isopropyl alcohol. Thestent is sonicated in the ultrasonic cleaner for two more minutes. Thetreated stent is then passivated in a 60° C.±3° C. 20% by volume NitricAcid bath for 30 minutes. The stent is then rinsed 10 times with copiousamounts of deionized water. The stent is then placed in 600 mL of asolvent such as isopropyl alcohol and sonicated in the ultrasoniccleaner for 5 minutes and allowed to air dry.

In another embodiment, not shown, the surface 5 of the stent isuniformly abraded in a controlled manner via shot peening. Roughening ofa stent surface 5 is accomplished using metal particles called shot thatrange in size from approximately 1 to 5 microns and is made from anatomic element having at least a weight of 43 g/mol. For example, theshot may be in the form of particulate tantalum, particulate tungsten,particulate platinum, particulate iridium, particulate gold, particulatebismuth, particulate barium, particulate zirconium and alloys thereof.Examples of suitable alloys include a platinum/nickel alloy and aplatinum/iridium alloy.

In another embodiment, not shown, a stent surface 5 can be treated tocreate mechanical injectors that range in size from about 3 to about 10microns.

In another embodiment, not shown, a stent surface 5 can be laser etchedto create regular or irregular patterns of asperities/mechanicalinjectors of about 5 to about 25 microns.

In another embodiment, not shown, the stent surface 5 can be treated tohave a different roughness factor on the ablumenal surface than thelumenal surface. For example the whole surface 5 may be treated via anyof the above disclosed methods. Then a subsequent masking of the lumenalsurface is performed so that a second surface treatment can be directedto the ablumenal surface. The subsequent treatment would typicallyutilize the more aggressive texturing process. The differing surfacesthus obtained can be used to impart differing useful properties to theinside (i.e. lumenal) vs. outside (ablumenal) surfaces of the stent. Inone embodiment, the lumenal surface roughness is optimized to improvecell ingrowth and adhesion, for example as described in (US PatentApplication No. 2005/0211680), and the ablumenal surface roughness maybe optimized to provide drug transfer from the ablumenal surface of thestent to the surrounding tissues as described herein.

The stent surface 5 may be treated by placing desired amount of shotover a predetermined portion of the stent surface 5 and in the desiredpattern. Pressure is applied to the particles using plates or rollers tomake indentations in the stent surface 5. Roughness can also be achievedby jet blasting the particles at the stent surface 5 at a velocitysufficient to make indentations. An example of shot peening a metalsurface is described in U.S. Pat. No. 6,911,100.

In a further embodiment, not shown, this uniform, controlled surfaceroughness can also be achieved similar to above by employing a laserrather than the use of shot. A series of electric discharges are appliedto the desired portion of the outer or inner stent surface 5. Theelectric discharges contact the surface with sufficient energy tovaporize the material on the surface of the stent, creating pits,sometimes called voids, the combined effect of which is a rough surfacehaving increased surface area. An example of this process is describedin U.S. Pat. No. 6,913,617.

In another embodiment, not shown, the surface 5 of the stent isuniformly treated by compression. The stent is affixed to a mandrel,which is inserted into a die that is equipped with preformed raisedportions that form indentations in the desired amount, shape, size andpattern on the stent surface 5. The indentations may be made in a numberof ways such as welding them onto the stent surface 5 or sandblasting.The die is then closed around the stent forming indentations of thedesired depth and covering the desired surface area. The stent istreated over its entire surface, or a portion of the surface, dependingon the manufacture of the die. An example of this process is describedin U.S. Pat. No. 7,055,237.

In another embodiment, shown in FIGS. 3A and 3C, a stent surface 5 istreated with a pneumatic press or hydraulic press 8. Pneumatic pressesare well known in the art as described in U.S. Pat. No. 4,079,617.Hydraulic presses are also well-known in the art as described in U.S.Pat. No. 7,033,155. As seen in FIG. 3A, the stent is positioned on amandrel 1 that is either stationary or rotating. A computer controlledpneumatic or hydraulic press 8 is configured to treat the surface 5 ofthe stent in one of several predetermined ways, for example, randomly orin a desired pattern. Referring to FIGS. 3B-3D, the punch assembly 9 ofthe press may be configured to contain one or more peeners 10, 11, heredefined as indentation creating mechanisms. In a preferred embodiment,the punch assembly contains a plurality of peeners 10, 11. It will beappreciated that the peeners 10, 11 may be of uniform or varied lengthin order to form the surface microstructure. Each peener 10, 11 remainsin a retracted position until the computer is programmed to treat thestent surface 5. According to the selected program, the peeners 10, 11will be depressed onto the stent surface 5 (not shown) with enough forceto result in an indentation. Generally, the punch assembly 9 isconfigured to be no more than the width of the desired stent. Forexample, if the stent strut 3 (not shown) is 15 micron, the plurality ofpeeners 10, 11, will total no more than 15 micron on width as well. Thenumber of peeners 10, 11 on a given punch assembly 9 will vary dependingon the width of the stent. Similarly, the punch assembly 9 may beconfigured to be a preformed head affixed to the press wherein the headsare interchangeable depending on which pattern is desired. Also, thehead can be stationary and the stent is turned or, in the alternative,the head can be moveable, this is embodied in a single peener 10, 11affixed to the press that will randomly make impressions on the stentsurface 5.

In another embodiment, not shown, the entire length of the tubing usedto create stents, for example tubing that is 2.5 meters in length, istreated prior to laser cutting it into a plurality of desired stentlengths. The stent is horizontally or vertically attached to one or moremandrels 1 and abraded using one of the methods disclosed in thisapplication. In terms of the abrading techniques, the stent is treatedrandomly, uniformly or in a desired pattern. Further, the length andsides of the stent is treated lengthwise, vertically or spirally.Moreover, the stent surface 5 is treated either by moving it over astationary roughening mechanism, or in the alternative, the entire stenttube length is stationary and the roughening mechanism may be moved overthe length of the tube in one of the manners disclosed, for examplehorizontally, vertically, spirally.

Potentiodynamic corrosion testing was performed on the treated stent toconfirm the desirability of the passivation step and its effectiveness.The data shows that the treated, passivated stent breakdown potential iswell within ASTM specified voltage levels standards. Therefore, afterthe roughening process and passivation, the treated stent does notexhibit a greater likelihood of corrosion when compared to the untreatedcontrol stent, and the roughening process does not increase thepotential for restenosis and thrombosis. After passivation, thebiocompatibility of the microstructured metal surface was observed to beequivalent to that observed with stents having smooth electropolishedsurfaces.

The approximate thickness of an untreated stent wall is generally around0.05 mm. As seen in FIGS. 2B-2C, the treatment of the stent surface 5 inthe manner disclosed results in a treated stent surface with a peak 6height averaging approximately 1.30 μm and a valley 7 depth averaging2.08 μm, respectively. To measure the effects, if any, that theroughening process has on the stent's structural integrity, axialfatigue testing and auger analysis were performed on a treated stent.Axial fatigue testing was focused at the portion of the stent that isthe most susceptible to breakage, which is the link 4 between stentstruts 3 (not shown). After over 3 million cycles in simulatedphysiological conditions, the untreated stent control and the roughedstent both remained intact. Since a portion of the treated stent isremoved in the roughening process, and it has been discovered that thetreated stent is able to withstand the same fatigue conditions as anuntreated intact stent with more surface area is able to withstand, itis understood that the roughening process actually increases the fatigueresistance of the stent due to the disrupted microcrystalline structuresof the stent body. Finally, auger analysis was performed on the treatedstent to characterize the surface chemistry, which revealed similarratios of identical elements in the passivated unroughened stent and thepassivated roughened stent. This demonstrates that the process ofpassivating the treated stent in the manner disclosed has no deleteriouseffects on the surface chemistry of the stent.

Example 2 (further details of which are provided below) provides surfaceroughness Ra and roughness factor Rt measurements for four stentsprepared as described above by surface abrasion with a pressurizedparticle blast. As seen, the surface roughness values were all at least20 μin (0.5 μm) and are typically between about 20-40 μin (0.5 μm-1.0μm), and a roughness range between 300-700 μin (7.5 to 17.5 μm), andtypically between 300 and 500 μin (7.5 μm and 12.5 μm). In accordancewith one aspect of the invention, these roughness values, andparticularly the roughness range values, have been found optimal forachieving optimal anti-restenosis results in subjects.

Without wishing to be limited to a particular theory as to this effect,it appears that the surface asperities or projections in the 300-700 μinpeak to valley range are optimal for “injecting” drug in the drugcoating into the surrounding vessel. Thus, for example, as theprojections are exposed, either by drug dissolution from the coating orby fractures in the coating during stent placement, the projections, byimpacting or penetrating the local vessel area, may facilitate entry ofthe drug into the vessel. The result is that the defined roughness rangeof the stent surface, combined with the polymer-free drug coating,maintains or further reduces the rate of occurrence and/or extent ofrestenosis or thrombosis seen with a polymer-coated, limus-elutingstent, but without the presence of a polymer carrier, and furtherreduces the rate of occurrence and/or extent of restenosis or thrombosisseen with a polymer-free coating on a less-roughened surface, i.e.,having a lower surface roughness range. Further, studies conducted insupport of the present invention indicate that a stent havingsurface-roughness features with peak-to-height values in the range800-1,000 μin (20-25 μm or more) may be less effective in reducingrestenosis.

Thus, in one aspect, the invention is directed to improving theeffectiveness, in terms of reduced incidence and/or extent ofrestenosis, in treating a vascular injury with a drug-eluting stent,e.g., a limus-eluting stent. The improvement includes the steps ofroughening at least the ablumenal surface portions of the stent to asurface roughness of at least about 20 μin (0.5 μm), and a surfaceroughness range of between about 300-700 μin (7.5-17.5 μm), and coatingthe roughened regions of the stent filaments with a polymer-free coatingof the limus drug, to a coating thickness greater than the range ofsurface roughness of the roughened stent surface, that is, to a coatingthickness that forms a substantially unbroken drug coating.

Preferably, an API (i.e., active pharmaceutical ingredient) such as theantiproliferative Biolimus A9™ is applied at least to the ablumenalportion of the stent. The API may be applied to the stent surface by anyappropriate means including by spraying the treated surface of the stentwith a solution of the API. The API solution may also be applied bydipping the entire stent into the desired API or by applying it directlyto the stent surface 5 manually. Biolimus A9™ has an amorphous tosemi-crystalline structure that does not crack or fracture like someother crystalline limus compounds. Therefore, the properties of BiolimusA9™ permit adhesion to the stent's roughened treated surface in theunexpanded state and the expanded state.

Preferably, the API material is applied to the ablumenal portion of thestent via autopipetting, as described in co-owned U.S. Pat. No.6,939,376. A solution ranging in a concentration of approximately 100mg/ml to approximately 200 mg/ml is made by dissolving the desired APIin an appropriate solvent, such as ethyl acetate or acetonitrile. Thesolution is placed in a reservoir with a pump designed to deliver thesolution at a predetermined rate. The pump is controlled by amicrocontroller, such as the 4-Axis Dispensing Robot Model availablefrom I&J Fisnar Inc. A solution delivery tube for delivery of thesolvent mixture to the stent surface 5 is attached to the bottom of thereservoir. The reservoir and delivery tube are mounted to a moveablesupport that moves the solvent delivery tube continuously or in smallsteps, for example, 0.2 mm per step along the longitudinal axis.

An uncoated stent is gripped by a rotating chuck contacting the innersurface of the stent at least at one end. Axial rotation of the stent isaccomplished by rotating the stent continuously, or in small degreesteps, such as 0.5 degree per step. Alternatively, the delivery tube isheld at a fixed position and, in addition to the rotational movement,the stent is moved along its longitudinal direction to accomplish thecoating process.

Prior to use, the solution delivery tubes are drawn and shaped under aBunsen burner to form a small tapered opening at the tip of the tube tofacilitate precise application of the drug/solvent mixture, which canthen be applied over the length and sides of the stent as needed withthe formed tip of the tube. It is within the scope of the invention touse more than one of the fluid dispensing tube types working in concertto form the coating, or alternately to use more than one moveablesolution reservoir equipped with different tips, or containing differentviscosity solutions or different chemical makeup of the multiplesolutions in the same process to form the coating.

In another embodiment, not shown, a non-porous layer of parylene,parylene derivative, or another biocompatible polymer is applied to thetreated stent surface, and the desired API is applied or layered ontothat. Optionally, an additional layer of slightly non-porous polymer isapplied directly over the API, which aids in controlled release overtime. According to the present invention, the stent comprises at leastone layer of an API posited on its surface, and the other surfaces willeither contain no API or one or more different APIs. In this manner, oneor more APIs may be delivered to the blood stream from the lumenalsurface of the stent, while different treatments for differentconditions are delivered on the vascular injury site/outside surface ofthe stent.

In another embodiment the stent is capable of being coated with an APImolecule without the need of a polymer. As seen in FIG. 4, the processof roughening all or a portion of the stent in one of the methodsdisclosed above allows for the API to adhere directly to the surface ofthe treated stent 14. In one general embodiment, the API is a limusdrug, such as described in U.S. Pat. Nos. 4,650,803, 5,288,711,5,516,781, 5,665,772 and 6,153,252, in PCT Publication No. WO 97/35575,in U.S. Pat. No. 6,273,913B1, and in U.S. Patent Application/PublicationNos. 60/176,086, 2000/021217A1, and 2001/002935A1. Exemplary limus drugsare the 42-O-alkoxyalkyl drugs, such as Biolimus A9™. Additional APIdrugs that may be employed, either alone, or in combination with a limusdrug, include antiplatelet or antithrombotic agents, oranti-inflammatory agents such as dexamethasone, dexamethasone acetate,dexamethasone sodium phosphate, or another dexamethasone derivative oran anti-inflammatory steroid. Either the inside and/or outside surfacesof the stent can also be used to deliver other types of API moleculessuch as thrombolytics, vasodilators, antihypertensive agents,antimicrobials or antibiotics, antimitotics, antiproliferatives,antisecretory agents, non-steroidal anti-inflammatory drugs,immunosuppressive agents, growth factors and growth factor antagonists,antitumor and/or chemotherapeutic agents, antipolymerases, antiviralagents, photodynamic therapy agents, antibody targeted therapy agents,prodrugs, sex hormones, free radical scavengers, antioxidants, biologicagents, radiotherapeutic agents, radiopaque agents and radiolabelledagents.

The stent may be included in an assembly consisting of a stent bodysurrounding a deflated balloon affixed to the distal portion of acatheter which is used to implant the stent at the vascular injury site.The stent is introduced into the cardiovascular system of a patient viathe brachial or femoral artery using the catheter. The catheter assemblyis advanced through the coronary vasculature until the deflated balloonand stent combination is positioned across the vascular injury site orsite of vascular disease or site of vascular narrowing. The balloon isthen inflated to a predetermined size to expand the stent to a diameterlarge enough to be in continuous contact with the lumen. The balloon isthen deflated to a smaller profile to allow the catheter to be withdrawnfrom the patient's vasculature, leaving the stent in place. An exampleof a typical stent implantation procedure is described in U.S. Pat. No.6,913,617.

IV. Methods of Use

This section describes vascular treatment methods in accordance with theinvention, and the performance characteristics of stents constructed inaccordance with the invention.

The methods of the invention are designed to minimize the risk and/orextent of restenosis in a patient who has received localized vascularinjury, or who is at risk of vascular occlusion due to the presence ofadvanced atherosclerotic disease. Typically the vascular injury isproduced during an angiographic procedure to open a partially occludedvessel, such as a coronary or peripheral vascular artery. Alternately,the stent may be introduced into a site of vascular narrowing, andexpanded using the balloon to directly open up the narrowed portion ofthe vessel (i.e. the vascular injury disease site). In the firstmentioned angiographic procedure, a balloon catheter is first placed atthe occlusion site, and a distal-end balloon is inflated and deflatedone or more times to force the occluded vessel open. This vesselexpansion, particularly involving surface trauma at the vessel wallwhere plaque may be dislodged, often produces enough localized injurythat the vessel responds over time by cell proliferation and reocclusionin the vicinity of the implanted stent. Not surprisingly, the occurrenceor severity of restenosis is often related to the extent of vesselstretching involved in the angioplasty procedure. Particularly whereoverstretching is 10% or more, restenosis occurs with high frequency andoften with substantial severity, i.e., vascular occlusion. In the secondmentioned alternative procedure of direct stent placement without priorangioplasty (i.e. “direct stenting”) there is nevertheless stillvascular injury induced by the expansion of the stent and balloon at thevascular injury disease site which results in restenosis and cellularproliferation at the site of the stent implantation, very similar inseverity to that seen from the first mentioned procedure.

The present invention is intended to be used without limitations to anyparticular method of treating an injury at the vascular site, and can beused with either of the techniques described above, or with alternativetechniques for vascular disease and injury as is known. In practicingthe present invention, the stent is placed in its contracted statetypically at the distal end of a catheter, either within the catheterlumen, or in a contracted state on a distal end balloon. The distalcatheter end is then guided to the injury site, or to the site ofpotential occlusion, and released from the catheter, e.g., by pullingback a sheath covering the stent to release the stent into the site, ifthe stent is self-expanding, or by expanding the stent on a balloon byballoon inflation, until the stent contacts the vessel walls, in effect,implanting the stent into the tissue wall at the site.

Once deployed at the site, the drug coated stent begins to releaseactive compound (API) into the cells lining the vascular site, toinhibit cellular proliferation and/or for other therapeutic benefitssuch as reduction of inflammation, limitation of thrombosis formation,reduction in cell apoptosis, etc. FIG. 5 shows Biolimus A9™ releasekinetics from two stents, one with the drug coated onto a surfacetextured stent and the other a Biomatrix® II stent with a polymercoating containing Biolimus A9™.

FIG. 6 shows the percentage of drug release of Biolimus A9™ from apolymer coated stent (i.e., Biomatrix®) and a textured stent. As seen inthe graph, after only two months, 100% of the Biolimus A9™ was releasedfrom the textured stent. In contrast, after three months, approximately30% of the drug remained on the polymer coated stent.

FIG. 7 shows the peak blood concentration of Biolimus A9™ as measured bymass spectroscopy for each of the polymer coated Biomatrix® II andtextured non-polymeric stent. As seen in the figure, the Biolimus A9™blood concentration peaks at about four hours with the textured stent.The peak blood concentration of Biolimus A9™ with the polymer coatedBiomatrix® II is at about two months.

FIGS. 9A-9F show in cross-section, a vascular region having an implantedbare metal stent (FIGS. 9A-9B), a metal Biomatrix® II stent having apolymer coating of 225 μg PLA and 225 μg Biolimus A9™ (FIGS. 9C-9D), anda textured stent with 225 μg Biolimus A9™ (FIGS. 9E-9F), where thecoated filaments are seen in cross section. The figures illustrate therelease of anti-restenosis compound from each filament region into thesurrounding vascular wall region. Over time, the smooth muscle cellsforming the vascular wall begin to grow into and through the lattice orhelical openings in the stent, ultimately forming a continuous innercell layer that engulfs the stent on both sides. If the stentimplantation has been successful, the extent of late vascular occlusionat the site will be less than 50%, that is, the cross-sectional diameterof flow channel remaining inside the vessel will be at least 50% ofexpanded stent diameter at time of implant.

Trials in a porcine restenosis animal model as generally described bySchwartz et al. (“Restenosis After Balloon Angioplasty-A PracticalProliferative Model in Porcine Coronary Arteries”, Circulation 82:(6)2190-2200, December 1990.) Studies have been conducted in the porcinemodel which demonstrate the ability of the stent of this invention tolimit the extent of restenosis, and the other advantages of the stentover currently proposed and tested stents. The studies are summarized inExample 3, explained in further detail below.

Briefly, the studies compare the extent of restenosis at 28 days in ananimal model following stent implantation, in bare metal stents,polymer-coated stents, and textured stents.

FIGS. 9A-9F show that both the polymer coated stent and textured stentgreatly reduced levels of restenosis. In general, the vessels withpolymer drug-coated stent and textured stent treatments appeared to bewell-healed with a well established endothelial layer. There is evidenceof complete healing and vessel homeostasis at 28 days post implant.

Further trials demonstrate the ability of the stents described herein tolimit the extent of restenosis over an extended period of at least threemonths. The studies are summarized in Example 4, explained in furtherdetail below.

Briefly, the studies compare the extent of restenosis at 3 monthsfollowing stent implantation with bare metal stents (BMS) and polymerfree drug eluting (pfDES) stents. Histomorphometry data shown in Table 4(below) shows the pfDES greatly reduced levels of restenosis as comparedto the BMS.

The following examples illustrate various aspects of the making andusing the stent invention herein. They are not intended to limit thescope of the invention.

Example 1 In Vitro Drug Release of Biolimus A9™ from Stents

In vitro drug release was conducted with Biomatrix® II stents coatedwith a polymer containing the antiproliferative drug Biolimus A9™ andwith stents containing an ablumenal microstructure including BiolimusA9™ in a PBS pH 7.4/Tween medium at 37° C. Sampling was periodicallyconducted and the total amount of Biolimus A9™ was measured by HPLC.FIG. 5, as previously described, illustrates drug release from theBiomatrix® II stent and the microstructure stent.

Example 2 Roughness Factor Bench Test

The outer surface of a Bioflex II 6 crown stent was treated with anabrasive to create a selectively micro-structured outer surface of thestent for drug loading capacity, called Bio-Freedom Stent (FS). Thetherapeutic agent can be coated directly on the selectivelymicrostructured surface of the stent.

The roughness factor of the FS was characterized using a commerciallyavailable Veeco Metrology Group (Tucson, Ariz.) WYKO NT-2000 system,which is a non-contact optical profiler. VSI (vertical scanninginterferometer) mode with Vision 32 software, removing cylinder and tiltterms so that the stent surface appears flat. A low pass filter is usedwhich removes the effects of high spatial frequency roughness, smoothingover features that are smaller than a nine pixel window. The results aregiven in the table below for four different stents whose surfaceroughness is produced by sand blasting, where Ra is the mean surfaceroughness, and Rt is the range in surface roughness, as defined above.

Sand Blast 3 Sand Blast 4 Sand Blast 5 Sand Blast 6 in μinches inμinches in μinches in μinches Ra 30.2 25.4 25.0 28.3 Rt 688.8 336.8406.9 358.9

Example 3 Animal Implant Tests

Textured stents from Example 2 with and without Biolimus A9™ wereimplanted in out-bred juvenile swine. A balloon catheter was used toplace the stent according to the standard porcine overstretch model with10-20% overstretch. The juvenile swine target vessels were predilated byknown angioplasty techniques prior to stent placement.

After 28 days, the animals were euthanized according to approvedprotocols, the heart and surrounding tissue was removed from theanimals.

A microscope containing a digital camera was used to generate highresolution images of the vessel cross-sections which had been mounted toslides, with the results shown in FIGS. 9A-9F (previously described).The images were subjected to histomorphometric analysis by the procedureas follows: The stent and artery were dissected, and micro-tomed by ahistologist. The samples were stained for various growth signals, cellproliferation, and other cellular debris. Histomorphometric measurementswere made ofthe artery area in mm² (FIG. 10A), IEL (FIG. 10B), intimalarea in mm² (FIG. 10C), lumen area in mm² (FIG. 10D), intimal thicknessin microns (FIG. 10E), % area stenosis (FIG. 10F), histologic gradingbased on injury and inflammation (FIG. 10G), histologic grading based onintimal extracellular matrix and EB/GC reaction (FIG. 10H), histologicgrading based on endothelialization and intimal fibrin (FIG. 10I),histologic grading based on medial inflammation, necrosis and fibrosis(FIG. 10J), and histologic grading based on adventitial inflammation andfibrosis (FIG. 10K).

The following table shows the results of the treatment effect at 28 daysfollow-up. The data in the tables below under column heading “Lumen Areamm²” report the results of morphometric analysis of stents and vesselsremoved from the pigs at 28 days follow-up (f/u):

TABLE 1 Histomorphometry results Arterial Area Lumen/Artery Injury LumenArea Stent mm² Ratio Score mm² Textured stent 7.76 mm² 1.08 0.57 3.35 ±0.66 without BA9 (textured ablation surface) Textured stent with 8.49mm² 1.08 0.50 5.68 ± 0.68 textured ablation surface and 225 μg BiolimusA9 ™

FIG. 8 shows the graph of the % area occlusion for each of the stentwith textured surface and the stent with textured surface and 225 μgBiolimus A9™.

Example 4 Three Month Porcine Implant Study

A. Stent Implantation

Polymer Free BioMatrix Stents sandblasted as in Example 2 with 225 μgBiolimus A9™ or a bare BioFlex II stent was implanted in a CrossbredFarm Pig Model according to Table 3.

TABLE 3 Animal Implant Matrix for Porcine Coronary Artery StentsLocation/Stent Type Pig No. LAD LCX RCA Duration 1 BMS pf DES pf DESEarly death 2 BMS pf DES pf DES 3 months 3 BMS n/a* Pf DES 3 months 4 pfDES pf DES BMS 3 months 5 BMS pf DES pf DES 3 months BMS = bare metalstent, pf DES = polymer free drug eluting stent *LCX was not stentedbecause of unsuitable size for stenting.

CV Path Institute, Inc. received hearts from 5 pigs. Non-overlappingstenting was performed in 5 pigs, and stents were explanted for lightmicroscopic analysis at three months. Animal 1 died before scheduledfollow up at three months for reasons not associated with stent implantprocedure at 2 months. The left circumflex coronary artery (LCX) ofanimal #3 was not stented because the LCX was of an unsuitable size.

B. Materials and Methods: Light Microscopy

For light microscopy, the stented vessel segments were embedded inmethylmethacrylate plastic and sections from the proximal, middle, anddistal stent were cut, mounted on charged slides, and stained withhematoxylin and eosin and Elastic Van Gieson (EVG). The non-stentedproximal and distal sections of the artery were embedded in paraffin,sectioned at four to five microns, and stained with hematoxylin andeosin and EVG. All sections were examined by light microscopy for thepresence of inflammation, thrombus, neointimal formation and vessel wallinjury.

Morphometric Analysis

Morphometric software (IP Lab for Macintosh, Scanalytics, Rockville,Md.) was calibrated using NIST traceable microscope stage micrometers of2.0 mm linear and 2.0 mm diameter circle with all objectives. KlarmannRulings, Inc., (Manchester, N.H.) certified all micrometer graduations.Areas of measurement included the EEL (external elastic lamina), IEL(internal elastic lamina) and lumen. The neointimal thickness wasmeasured at and between stent struts and averaged for each animal. Bysubtracting IEL from EEL, the medial area was determined. Percentstenosis was derived from the formula [1-(lumen area/stent area)]×100.Vessel injury score was determined using the Schwartz method (Schwartz RS et al., J Am Coll Cardiol 1992; 19:267-274). Inflammation, fibrin, andinjury scores were generated for each section based on a graded analysisof 0=no inflammation/fibrin/injury to value 3=markedInflammation/fibrin/injury. An inflammation score of 4 was given tosections with 2 or more granulomatous reactions present. Endothelialcoverage was semi-quantified and expressed as the percentage of thelumen circumference.

C. Statistical Analysis

The morphometric continuous data were expressed as mean±SD. Statisticalanalysis of the normally distributed parameters was performed using aStudent's t-test. The Wilcoxon test was used in the analysis fornon-normally distributed parameters or discrete values. Normality ofdistribution was tested with the Wilk-Shapiro test. A p value of <0.05was considered statistically significant.

D. Radiographic Findings

All stents appeared widely and evenly expanded without evidence offracture or being bent.

E. Light Microscopy Observations

1. Polymer Free DES

All stents were widely expanded and patent without any evidence ofthrombus at 3 months after implantation. Neointimal formation was mildwith a mean neointimal thickness of 0.16 mm and composed by looselypacked smooth muscle cells and proteoglycan-rich matrix. Vessel injurywas mild. Mild fibrin deposition localized around the struts wasobserved. Although granulomatous response was seen in the LCX of animal#5, inflammation was minimal overall in the other vessels. Giant cellswere occasionally observed and documented. Endothelialization wascomplete without lumenal inflammatory cells and/or platelet adhesion.Notably, a dense calcification was seen in neointima at the proximalsection in LCX of animal #2 which contained a bare metal stent.

2. Bare Metal Stents

All stents were widely expanded and patent without any evidence ofthrombus at 3 months after implantation. Neointimal formation was mildwith a mean neointimal thickness of 0.21 mm and composed of tightlypacked smooth muscle cell. Medial rupture was observed in the LeftAnterior Descending coronary artery (LAD) of animal #2. This vesselshowed severe inflammation mainly around the struts probably due to theinjury created by the implant procedure. However, except for thisanimal, vessel injury and inflammation were mild overall. Fibrindeposition and malapposition were not seen in any stents.Endothelialization was completed without presence of lumenalinflammatory cells and/or platelet adhesion.

F. Histomorphometry

TABLE 4 Morphometric comparison of BMS and polymer free DES at 3 monthsPolymer free DES Treatment (n = 7) BMS (n = 4) p-value EEL Area (mm²)9.52 ± 1.27 7.32 ± 0.86 0.01 IEL Area (mm²) 8.16 ± 1.09 6.15 ± 0.81 0.01Lumen Area (mm²) 6.27 ± 1.59 4.17 ± 0.98 0.04 *p-value derived byWilcoxon test statistical analysis

The results of this animal study demonstrated a significant increase inLumen Area (i.e. reduction in restenosis) at 3 months after stentimplant in a porcine model for the Polymer Free drug eluting stent(Freedom DES) as compared to bare metal control stent implants (BMS).

The description of the invention is merely exemplary in nature and thus,variations that do not depart from the gist of the invention areintended to be within the scope of the invention. Such variations arenot to be regarded as a departure from the spirit and scope of theinvention.

What is claimed is:
 1. A method for making an expandable, metal stenthaving metal filaments coated with a polymer-free limus drug where therate of occurrence and/or extent of restenosis or thrombosis resultingfrom vascular injury in a subject, is reduced relative to that observedby placing at a site of injury, a bare-metal expandable stent formed ofinterconnected metal filaments or by having a coating on the outersurface of the stent filaments of a polymer carrier containing a limusdrug, the method comprising: roughening regions of the outer surface ofthe stent filaments to a surface roughness (Ra) of between 20-40 μin(0.5-1 μm), and a surface roughness range (Rt) of between 300-700 μin(7.5-17.5 μm), and coating the roughened regions of the stent filamentswith a polymer-free limus drug, to a coating thickness greater than therange of surface roughness of the roughened stent surface.
 2. The methodaccording to claim 1, wherein said roughening is carried out by abradingthe outer surface regions of the stent filaments with a pressurizedstream of abrasive particles.
 3. The method according to claim 1,wherein said roughening is carried out by forming a hydrocarbon-filmmask over regions of the surface of the stent filaments, selectivelyremoving stent material not covered by the mask, and removing the mask.4. The method according to claim 1, wherein said roughening is carriedout by laser etching the outer surface regions of the stent filaments.5. The method according to claim 1, wherein said roughening is carriedout by peening the outer surface regions of the filaments to imprint apattern thereon.
 6. The method according to claim 1, wherein saidcoating is carried out by applying a viscous solution of the drug ontothe outer surfaces of the stent filament, and drying the appliedsolution to form a solid drug coating on the stent filaments.
 7. Themethod according to claim 1, wherein said coating is carried out toapply a final amount of limus drug on the stent between 80 to 240 μg/cmstent length.
 8. The method according to claim 9, wherein said coatingis carried out to produce a final drug coating having a thicknessbetween 5 and 15 μm.
 9. The method according to claim 1, wherein thelimus drug coating said stent is Biolimus A9.